Identification of quantitative trait loci for survival in the mutant dynactin p150Glued mouse model of motor neuron disease.
Identification of quantitative trait loci for survival in the mutant dynactin p150Glued mouse model of motor neuron disease.
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DOI：
10.1371/journal.pone.0274615
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
肌萎缩侧索硬化症（ALS）是最常见的退行性运动神经元疾病。虽然大多数ALS病例是散发的，但5-10%的病例是家族性的，与40多个基因相关的突变。在携带相同突变的家庭中，ALS症状存在差异；这种疾病可能发生在一个兄弟姐妹身上，而不会发生在另一个兄弟姐妹身上，尽管两个兄弟姐妹都有这种突变。虽然这种表型变异的原因尚不清楚，但它可能与疾病表达的遗传修饰因子有关。ALS致病基因的鉴定导致了运动神经元疾病转基因小鼠模型的发展。与家族性ALS家族相似，ALS转基因小鼠模型的疾病表型存在背景依赖性差异，这表明，与人类ALS一样，表型差异可能归因于基因修饰。这些基因修饰因子可能不会引起ALS，而是它们的表达加剧或改善突变的ALS引起基因的作用。我们已经报道了在G93A-hSOD1和G59S-hDCTN1小鼠模型中，SJL小鼠表现出比C57BL6小鼠更严重的表型。通过G93A-hSOD1转基因小鼠在SJL和C57BL6株上的互交，我们在小鼠17号染色体上发现了一个导致寿命显著变化的主要数量性状位点（QTL）。本研究将转基因G59S-hDCTN1小鼠在SJL和C57BL6株上进行互交，鉴定出小鼠17和18号染色体上的存活qtl。G93A-hSOD1和G59S-hDCTN1小鼠的17号染色体存活QTL部分重叠，提示尽管运动神经元变性是由不同蛋白突变引起的，但这两种ALS模型可能共享位于该区域的遗传修饰因子。重叠区域包含87个具有非同义变异的基因，预计是有害的和/或有害的。NOTCH3和Safb/SAFB1这两个基因与运动神经元疾病有关。确定运动神经元疾病的遗传修饰因子，特别是SOD1和动力蛋白-1转基因小鼠共有的修饰因子，可能会导致确定新的治疗靶点，从而改变这种毁灭性疾病的进程。
Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disorder. Although most cases of ALS are sporadic, 5–10% of cases are familial, with mutations associated with over 40 genes. There is variation of ALS symptoms within families carrying the same mutation; the disease may develop in one sibling and not in another despite the presence of the mutation in both. Although the cause of this phenotypic variation is unknown, it is likely related to genetic modifiers of disease expression. The identification of ALS causing genes has led to the development of transgenic mouse models of motor neuron disease. Similar to families with familial ALS, there are background-dependent differences in disease phenotype in transgenic mouse models of ALS suggesting that, as in human ALS, differences in phenotype may be ascribed to genetic modifiers. These genetic modifiers may not cause ALS rather their expression either exacerbates or ameliorates the effect of the mutant ALS causing genes. We have reported that in both the G93A-hSOD1 and G59S-hDCTN1 mouse models, SJL mice demonstrated a more severe phenotype than C57BL6 mice. From reciprocal intercrosses between G93A-hSOD1 transgenic mice on SJL and C57BL6 strains, we identified a major quantitative trait locus (QTL) on mouse chromosome 17 that results in a significant shift in lifespan. In this study we generated reciprocal intercrosses between transgenic G59S-hDCTN1 mice on SJL and C57BL6 strains and identified survival QTLs on mouse chromosomes 17 and 18. The chromosome 17 survival QTL on G93A-hSOD1 and G59S-hDCTN1 mice partly overlap, suggesting that the genetic modifiers located in this region may be shared by these two ALS models despite the fact that motor neuron degeneration is caused by mutations in different proteins. The overlapping region contains eighty-seven genes with non-synonymous variations predicted to be deleterious and/or damaging. Two genes in this segment, NOTCH3 and Safb/SAFB1, have been associated with motor neuron disease. The identification of genetic modifiers of motor neuron disease, especially those modifiers that are shared by SOD1 and dynactin-1 transgenic mice, may result in the identification of novel targets for therapies that can alter the course of this devastating illness.
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DOI：
10.1002/wdev.375
发表时间：
2020-09
期刊：
Wiley interdisciplinary reviews. Developmental biology
影响因子：
--
作者：
Co M;Anderson AG;Konopka G
通讯作者：
Konopka G
影响因子：
3.3
作者：
Biswas S;Emond MR;Duy PQ;Hao le T;Beattie CE;Jontes JD
通讯作者：
Jontes JD
影响因子：
--
作者：
Begliuomini, Chiara;Magli, Giorgio;Sotgiu, Stefano
通讯作者：
Sotgiu, Stefano
DOI：
10.1016/j.molbrainres.2004.07.002
发表时间：
2004-11-04
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Alexander, GM;Erwin, KL;Heiman-Patterson, TD
通讯作者：
Heiman-Patterson, TD
影响因子：
3.5
作者：
Estruch, Sara B.;Graham, Sarah A.;Fisher, Simon E.
通讯作者：
Fisher, Simon E.